Residual association at C9orf72 suggests an alternative amyotrophic lateral sclerosis-causing hexanucleotide repeat

Area of Science:

• Neurogenetics
• Genomic association studies

Background:

• Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons.
• The C9orf72 gene hexanucleotide repeat expansion is a known genetic cause of ALS.
• Single-nucleotide polymorphism rs3849942 is associated with ALS and tags this repeat expansion.

Purpose of the Study:

• To investigate potential additional disease-causing genetic variations at the C9orf72 locus in ALS patients.
• To determine if genetic associations persist after accounting for the known C9orf72 repeat mutation.

Main Methods:

• Genome-wide association testing was performed on DNA from ALS patients.
• Analysis was conducted first with all samples, then excluding cases with the C9orf72 mutation.
• Specific focus on single-nucleotide polymorphisms rs3849942 and rs903603.

Main Results:

• Both rs3849942 and rs903603 showed strong association with ALS when all samples were included.
• Association for rs3849942 was lost upon removal of mutation-carrying cases.
• rs903603 maintained significant association with ALS even after excluding mutation carriers, suggesting a distinct genetic factor.

Conclusions:

• The persistent association of rs903603 indicates a second, independent disease-causing repeat mutation at the C9orf72 locus.
• This finding expands our understanding of the genetic architecture of ALS.
• Further research is warranted to characterize this second mutation and its role in ALS pathogenesis.